The formation of oxygen radical species (ORS) is involved in the pathogenesis of many acute and chronic diseases, ranging from inflammatory-immunologic diseases to myocardial infarction and cancer. Some of the deleterious effects from the excessive formation of ORS include lipid peroxidation of the membrane lipids, oxidative damage to nucleic acids and carbohydrates, as well as oxidation of sulfhydryl proteins and other sensitive groups. The defence provided by antioxidant systems is essential for survival. Detoxification of the ORS in a cell is carried on by enzymatic and non-enzymatic systems which constitute the antioxidant defence system (Middleton Jr. E., Chithan K., and Heoharides T. C. The Effects of Plant Flavonoids on Mammalian Cells: Implications for Inflammation, Heart Disease, and Cancer. Pharmacol Rev 52:673-751, 2000).
Lipid peroxidation can be biologically important in the exacerbation of a tissue lesion due to the potential cytotoxicity of the final products resulting from peroxidation. For example, products of lipid peroxidation of the cells may be carcinogenic. Recently, emphasis has been put on the role that lipid peroxidation plays in the development of arteriosclerosis, strokes, myocardial infarction, damage to the brain and spinal cord after suffering ischemia, cancer, inflammation, iron toxicity, and hepatotoxicity induced by chemical and biological agents (Middleton Jr. E., Chithan K., and Heoharides T. C. The Effects of Plant Flavonoids on Mammalian Cells: implications for Inflammation, Heart Disease, and Cancer. Pharmacol Rev 52:673-751, 2000).
Chronic hepatic diseases cause thousands of deaths in the world every year and are the tenth leading cause of death in the United States. Currently, hepatic disorders, particularly those caused by viral infections, are a serious health issue, and their successful treatment constitutes a big challenge. There is no effective treatment for a majority of the hepatopathies. Currently some patients with viral hepatitis are treated with Interferon (IFN); however, IFN therapy has been successful only in about 25% of the cases.
IFN is not available to all the patients, as the six-month therapy required is expensive. In addition, this treatment has several secondary effects like severe flu-like symptoms, lethargy, hair loss, and bad taste in the mouth. IFN attacks the virus via the immune system, but it does not reverse the damage caused by the infection, like hepatic cirrhosis or diminished functionality of the spleen.
Other treatments, such as Ribavirin therapy, improve the results in medical and histological exams, especially in combination with IFN. However, costs of treatment are also high and there is a significant risk of suspending the treatment due to adverse effects (Mc Hutchison, J. G. and Poynard T. Combination therapy with interferon plus Ribavirin for the initial treatment of chronic Hepatitis C. Semin Liver Dis 1999; 19 (suppl 1): 57-65; Davil G. L. Combination therapy with interferon alpha and Ribavirin as treatment of interferon relapse in chronic hepatitis C. Semin Liver Dis 1999; 19 (suppl 1): 49-55).
The World Health Organisation (WHO) estimates that 3% of the world's population has been infected with Hepatitis C, and that there are around 170 million chronic carriers who are at risk for developing cirrhosis and/or liver cancer. The WHO cannot afford to treat 170 million people in the world with medications like Rebetron, which consists of Ribavirin and Interferon alpha 2B, whose treatment costs USD 2,000 per month, for 6-12 months; in addition, these treatments require extensive medical support to manage the adverse effects caused by the medications.
Since there is no therapy or synthetic medication effective and safe enough to treat hepatopathies, many patients have turned to alternative medicine based on natural elements. Despite significant progress in modern medicine, medicinal plants remain as a necessary element when it comes to developing accurate, safe and effective treatments for hepatic disorders. In recent years, there has been a shift towards the therapeutic evaluation of herbal products to treat liver diseases, some of which are proving safe and moderately effective.
Several scientific publications point out the fact that many groups of metabolites from vegetal origin show antioxidant and hepatoprotective activity. This is observed particularly amongst phenols, especially those belonging to the benzenoid group, where tournefolal, tournefolic acids A and B, and the ethylester from the tournefolic acid, isolated from the aerial parts, that is, the stem, leaves, flowers and fruit, of the Tournefortia sarmentosa, show antioxidant activity and inhibit the peroxidation of low-density lipoproteins (Lin Y. L., Chang Y. Y., Kuo Y. H., Shiao M. S. Anti-lipid-peroxidative principles from Tounefortia samentosa. J Nat. Prod. 2002 May; 65(5):745-7). Curcumin, also a benzenoid, shows a captivating activity on superoxide anions (Kunchandy E., Rao M. N. A. Int. J. Pharmaceut., 57: 173-176 (1989)) and nitric acid (Sreejayan N., Rao M. N. A. J. Pharm. Pharmacol., 49: 105-107 (1997)) in experimental models showing the inhibition of lipid peroxidation in rat liver (Reddy A. C., Lokesh B. R. Food Chem. Toxicol., 32: 279-283 (1994)).
Other phenolic elements, such as tannins, show antioxidant (Satoh, K., Sakagami, H., 1996. Ascorbyl radical scavenging activity of polyphenols. Anticancer Res. 16: 2885-2890) and hepatoprotective (Miyamoto, K. I., Nomura, M., Murayama, T., Furukawa, T., Hatano, T., Yashida, T., Koshiura, R., Okuda, T., 1993. Antitumor activities of ellagitannins against sarcoma-180 in mice. Biol. Pharm. Bull. 16: 379-387) activity, inhibiting lipid peroxidation in hepatic microsomes and mitochondria (Okuda T., Kimuar Y., Yoshida T., Hatano T., Okunda H., Arichi S. Studies on the activities of tannins and related compounds from medicinal plants and drugs. I. Inhibitory effects on lipid peroxidation in mitochondria and microsomes of liver. Chem. Pharm. Bull. 31: 1625-1631 (1983)). Tannic acid reduced the incidence of hepatic neoplasia in mice (Hirose M., Ozaki K., Takaba K., Fukushima S., Shirai T., Ito, N. Modifying effects of the naturally occurring antioxidants gamma—oryzanol, phytic acid, tannic acid and n-tritriacontane-16, 18-dione in a rat wide-spectrum organ carcinogenesis model. Carcinogenesis 12: 1971-1921 (1991)). Results from extensive clinical research showed the effectiveness and safety of the polyphenols when it comes to treating hepatobiliary dysfunctions and digestive problems, such as a sensation of fullness, loss of appetite, nausea and abdominal pain. In addition, these elements have been found to have preventive and hepatoprotective effects against gastropathy induced by non-steroidal anti-inflammatories (Ruiyc. Advances in pharmacological studies of silymarin. Mem Inst Oswaldo Cruz 1991; 86:79-85; Scevola D, Barbacini G, Grosso A, Bona S, Perissoud D. Flavonoids and hepatic cyclic monophosphates in liver injury. Boll Ins Sieroter Milan 1984; 63:77-82).
Coumarins are another kind of polyphenolic compounds that can be found in abundance in the vegetable kingdom. Many of them show interesting biological activity, for instance, the 4-methoxycoumarins have cholerectic properties (Takeda, S.; Aburada, M. J. Pharmacobio-Dyn. 4: 724 (1981)). The 7,8 dihydroxy-4-methylcoumarin and the 7,8-diacetoxy-4-methylcoumarin have antioxidant properties, and thus are considered effective scavengers of oxygen radicals (Raj, H. G.; Parmar, V. S.; Jain, S. C.; Priyadarsini, K. I.; Mittal, J. P.; Goel, S.; Poonam; Himanshu; Malhotra, S.; Singh, A.; Olsen, C. E.; Wngel, J. Bioorg. Med. Chem. 6: 833 (1998)). In addition, this group of molecules show protective effects against toxicity induced by a known oxidant (t-butylhydroperoxide) in HepG2 cells and primary human hepatocyte cultures (Bernard Refouvelet, Catherine Guyon, Yves Jacquot, Corinne Girard, Herve Fein, Francoise Bevalotb, Jean-Francois Robert a, Bruno Heyd, Georges Mantion, Lysiane Richert, Alain Xicluna, Synthesis of 4-hydroxycoumarin and 2,4-quinolinediol derivatives and evaluation of their effects on the viability of HepG2 cells and human hepatocytes culture. European Journal of Medicinal Chemistry 39: 931-937 (2004)).
The terpenoids are other group of metabolites derived from plants that also show antioxidant (Zhu M, Chang Q, Wong L K, Chong F S, Li R C. Triterpene antioxidants from Ganoderma lucidum. Phytotherapy Research 13: 529-31 (1999)) and hepatoprotective (James, L. P., Mayeux, P. R., Honson, J. A. Acetaminophen-induced hepatotoxicity. Drug Metabolism Disposition 31: 499-506 (2003)) activity. Triterpene celastrol shows a powerful inhibitory effect against lipid peroxidation in the hepatic mitochondria. In vitro and in vivo experiments, as well as other clinical tests, have shown the effects of gastroprotective (Zhu M, Chang Q, Wong L K, Chong F S, Li R C. Triterpene antioxidants from Ganoderma lucidum. Phytotherapy Research 13: 529-31 (1999)) and hepatoprotective activity of several terpenoids, such as the oleanic acid, ursolic acid, alpha-hederine, glycyrrhizin and lupeol (Liu, J., Liu, Y., Mao, Q. The effects of 10 triterpenoid compounds on experimental liver injury in mice. Fundamental and Applied Toxicology 22: 34-40 (1994)) (Sunitha S., Nagaraj M., Varalakshmi P. Hepatoprotective effect of lupeol and lupeol linoleate on tissue antioxidant defence system in cadmium-induced hepatotoxicity in rats. Fitoterapia 72: 516-523 (2001)).
There is a need for a safe and effective treatment for viral and non-viral hepatic disorders that address some of the disadvantages of current treatment methods.